Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation.

Abstract

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1(+/-)) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury. However, the downstream Ras effector pathway responsible for this phenotype is unknown. Based on in vitro assays demonstrating enhanced extracellular signal-related kinase (Erk) signaling in Nf1(+/-) macrophages and vascular smooth muscle cells and in vivo evidence of Erk amplification without alteration of phosphatidylinositol 3-kinase signaling in Nf1(+/-) neointimas, we tested the hypothesis that Ras-Erk signaling regulates intimal proliferation in a murine model of NF1 arterial stenosis. By using a well-established in vivo model of inflammatory cell migration and standard cell culture, neurofibromin-deficient macrophages demonstrate enhanced sensitivity to growth factor stimulation in vivo and in vitro, which is significantly diminished in the presence of PD0325901, a specific inhibitor of Ras-Erk signaling in phase 2 clinical trials for cancer. After carotid artery injury, Nf1(+/-) mice demonstrated increased intimal proliferation compared with wild-type mice. Daily administration of PD0325901 significantly reduced Nf1(+/-) neointima formation to levels of wild-type mice. These studies identify the Ras-Erk pathway in neurofibromin-deficient macrophages as the aberrant pathway responsible for enhanced neointima formation.

• Authors: Brian K Stansfield, Waylan K Bessler, Raghuveer Mali, Julie A Mund, Brandon D Downing, Reuben Kapur, David A Ingram Jr
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 1 Pg. 79-85 (Jan 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 24211110 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Neurofibromin 1
• ras Proteins

Topics

• Animals
• Blotting, Western
• Carotid Stenosis (metabolism, pathology)
• Disease Models, Animal
• MAP Kinase Signaling System (physiology)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Neointima (metabolism, pathology)
• Neurofibromatosis 1 (genetics, metabolism, pathology)
• Neurofibromin 1 (genetics, metabolism)
• Signal Transduction (physiology)
• ras Proteins (physiology)